Neural mechanisms of pain

Neural mechanisms of pain
MEDI6100 Sydney Broome Fremantle

Student learning outcomes
Describe 'pain pathways' in depth Outline central nervous system [CNS] control over pain perception See learning suggestions at the end of this slide show Main reference to read Schug SA, et al. APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2015), Acute Pain Management: Scientific Evidence (4th edn) ANZCA & FPM, Melbourne, pages 1-7 © EJ Visser and UNDA 2018 all rights reserved

© EJ Visser and UNDA 2018 all rights reserved
What is pain? ‘Pain is an unpleasant sensory & emotional experience associated with actual or potential tissue damage’ (IASP 2012) Pain is generated by the conscious brain in response to perceived tissue damage Pain is more than just a sensation Pain is a subjective, multidimensional, whole-person experience Pain is what the person-in-pain says it is Pain always occurs in a ‘context’ -bio-medical-psycho-social-environmental © EJ Visser and UNDA 2018 all rights reserved

Nociception ‘The process of encoding & transmitting noxious stimuli in the nervous system’ (IASP 2012) Converting the ‘energy’ released by tissue damage into electro-chemical signals in the nervous system -chemical (‘inflammatory soup’) -mechanical -thermal Pain & nociception are not the same thing Nociception is the sensory processing ‘bit’ (a brain input) Pain is the sensory & emotional experience (a brain output) Nociception is the (main) trigger & driver of pain CAN have pain without nociception & vice versa © EJ Visser and UNDA 2018 all rights reserved

Terminator II-Judgment Day (1991)
Nociception vs pain explained in a movie Terminator II-Judgment Day (1991) John Connor “Does it hurt when you get shot?” The Terminator “I sense injuries… The data could be called pain.” Data = nociception © EJ Visser and UNDA 2018 all rights reserved

Pain is nature’s tissue-damage ‘alarm’
© EJ Visser and UNDA 2018 all rights reserved © EJ Visser and UNDA 2018 all rights reserved

Nociceptive (pain) pathways
Limbic system Rene Descartes Brainstem Dorsal horn Rene Descartes

Inflammation Dolor (pain) Calor (heat) Rubor (redness)
Galen & Celsus Dolor (pain) Calor (heat) Rubor (redness) Tumor (swelling) Functio laesa (loss of function)

Transduction Converting (chemical, thermal, mechanical) energy of tissue damage into electro-chemical nerve signals Heat Acid (H+) TRPV1 DRG Spinal cord nociceptors Cold TRPV8 Aδ C Dorsal horn Mechanical © EJ Visser and UNDA 2018 all rights reserved

A & C fibres transmission A fibres Thick Myelinated Fast Localised ‘Sharp’ pain C fibres Thin Unmyelinated Slow Poorly localised Dull, aching or burning pain © EJ Visser and UNDA 2018 all rights reserved

Voltage-gated Na+ channels
transmission Local anaesthetics Anticonvulsants Neuroma ectopics

The ‘CPU’ of nociceptive system
Dorsal horn modulation The ‘CPU’ of nociceptive system © EJ Visser and UNDA 2018 all rights reserved

Dorsal horn first-order synapse Nuclear changes
© EJ Visser and UNDA 2018 all rights reserved

It’s the nervous system’s ‘chemical transistor’ (amplifier)
NMDA channel It’s the nervous system’s ‘chemical transistor’ (amplifier) Mediates central sensitization -’wind-up’ -memory (hippocampus) Glutamate is the agonist Blocked by ketamine © EJ Visser and UNDA 2018 all rights reserved © Eric J. Visser 2017 UNDA. All rights reserved

Glutamate Most abundant neurotransmitter in body (90%)
Excitatory (neurotoxic in high amounts) Amplification Sensitization Learning Memory Wind-up Long term potentiation Glia mops up glutamate © EJ Visser and UNDA 2018 all rights reserved

Central sensitization amplifier
Increased nociceptive output for a given nociceptive input Amplifier effect Capacitance effect ‘memory’ NMDA Hz lllllllllllllllllllll 50 Hz Wind-up Dorsal horn © EJ Visser and UNDA 2018 all rights reserved © Eric J. Visser 2017 UNDA. All rights reserved 22

Wind-up amplifier effect
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII Stimulus 3 Hz © EJ Visser and UNDA 2018 all rights reserved

Allodynia ‘touch pain’
Greek for ‘other pain’ Allodynia is the clinical sign for central sensitization If any of these non-painful stimuli feels painful, you have detected allodynia… ...and therefore central sensitization © EJ Visser and UNDA 2018 all rights reserved 24

‘Pain gate’ inhibition in dorsal horn

‘Pain gate’ dorsal horn

Descending inhibition
Flight (or fight) Midbrain to dorsal horn Inhibitory transmitters -norepinephrine -serotonin -endorphins CPM allows us to escape danger CPM allows us to sit on our bottoms -45 kg/cm2 pressure © EJ Visser and UNDA 2018 all rights reserved © Eric J. Visser 2017 UNDA. All rights reserved

Descending inhibition
NE © EJ Visser and UNDA 2018 all rights reserved

Biphasic pain response
Analgesia: Allows ‘flight’ from danger Twin Towers DI: NE, endorphins ‘Pain gate’ Hyperalgesia Tissue damage Analgesia Hyperalgesia: Rest injured body part (healing) Conditioning; learn to avoid injury © EJ Visser and UNDA 2018 all rights reserved Simonnet & Rivat Neuroreport 2003

Spinal cord nociceptive pathways
© Future Neurol 2007 Thalamocortical system Limbic system Primitive emotional brain Spinal-midbrain-limbic pathway midline tract slower transmission poorly localised pain visceral > somatic pain evolution: primitive Spinothalamic pathway lateral tract fast transmission well localised pain somatic > visceral pain evolution: ‘newer’ © EJ Visser and UNDA 2018 all rights reserved

The bane of pain is mainly in the brain
Loesser © EJ Visser and UNDA 2018 all rights reserved © Eric J. Visser 2017 UNDA. All rights reserved

Emotional, autonomic, visceral
Limbic system Pain ‘relay station’ Autonomic Cingulate gyrus Fear & anxiety panic Memory of pain © EJ Visser and UNDA 2018 all rights reserved

Localization Somatosensory cortex Sensory homunculus (body-map)

Nociceptive (pain) pathways
Descending inhibition DRG NE Aδ & C fibres Dorsal horn Central sensitization ‘amplification’ transduction transmission modulation tissue damage TRPV channels Inflammatory soup voltage gated Na ion channels © EJ Visser and UNDA 2018 all rights reserved

Don’t forget the neuroimmune system! Glia
Interleukin 1, 6, TNF Need this to happen to have chronic pain. Toll-like receptor 4

Key learning objectives
Know the definitions of pain & nociception Understand differences between them Appreciate that pain is a complex, multi-dimensional experience generated by the conscious brain, and not just a sensation Understand that pain is a tissue damage ‘alarm’ system Know that a person can experience pain when there’s NO tissue damage Understand the basic anatomy of nociceptive (‘pain’) pathways Understand the transduction, transmission & modulation of nociceptive signals in the nervous system © EJ Visser and UNDA 2018 all rights reserved

Key learning objectives
Understand the concept of the ‘pain gate’ in the dorsal horn Understand the concept of neuroplasticity & its role in pain Understand that central sensitization (CS) ‘amplifies’ nociception Understand that descending inhibition ‘dampens’ nociception Understand the concept of pain ‘wind-up’ Know that allodynia (touch pain) is the main clinical sign of CS Understand that nociception activates the (emotional) limbic system Understand that there is no specific ‘pain centre’ in the brain Understand the roles of the neuroimmune (glia) & adrenergic systems in nociception & pain © EJ Visser and UNDA 2018 all rights reserved

Pain is nature’s tissue damage alarm
Acute pain signals a ‘tissue damage emergency’ Unpleasant sensory & emotion experience -aversive conditioning (learning) Pain behaviours -escape -signals risk of tissue damage to others Pain (nociception) has protected Earth’s life-forms for millions of years Evolutionary survival advantage Highly preserved in phylogeny © EJ Visser and UNDA 2018 all rights reserved

Pain alarm Pain conditions us (and others in our social group) to avoid future tissue damage Learn from our mistakes Especially in childhood Nocebo response © EJ Visser and UNDA 2018 all rights reserved

Pain pathways Rene Descartes "Particles of heat activate a spot of skin attached by a fine thread to a valve in the brain… this opens the valve allowing animal spirits to flow from a cavity into the muscles causing them to flinch, and turn the head and eyes toward the affected body part, also moving the hand and turn the body protectively.” © EJ Visser and UNDA 2018 all rights reserved

Referred pain Definition: Pain experienced in a different part of the body to the site of nociception Sensory afferents from viscera & somatic tissues share a common connection in spinal dorsal horn Dorsal horn convergence © Eric J. Visser 2017 UNDA. All rights reserved

Glia and nociception Glia are non-neuronal cells in the central (CNS) and peripheral (PNS) nervous systems, that maintain homeostasis, form myelin, and provide support and protection for neurons. Glia in PNS Schwann cells- nerve Satellite cells-DRG Glia in CNS Astrocytes- involved in “normal” nociception Microglia Oligodendrocytes Ependymal cells Glia can be activated by; Peripheral nerve injury Trauma- physical or psychological Hypoxia Infection * Activated after PNS injury Glia are non-neuronal cells… In the PNS, there are schwann cells in the peripheral nerves and satellite cells located in the DRG . In the CNS, in the brain and spinal cord there are astrocytes that are involved in neuronal physiology and we can say regulate almost all aspects on neuronal functioning, including having a role in normal nociception. Here we have an astrocyte whose role is continuous reuptake of neurotransmitters excitatory glutamate and GABA around synapses between sensory afferents and inhibitory interneurons respectively allows a fast and regulated nociceptive neurotransmission toward upper brain regions. In the spinal cord and brain we also have microglia, but this is not activated during acute nociceptive responses. This is the same for other glia, such as oligos and ependymal cells. However, in certain circumstances such as peripheral nerve injury, these glia can be activated. Glia can also be activated after trauma, hypoxia etc Gosselin et al., (2010) Neuroscientist. 16(5): 519–531 © EJ Visser and UNDA 2018 all rights reserved

Immune and glial response after nerve injury
Satellite cells Schwann cells Resident Microglia and Astrocytes Active Microglia Transient activation Promotes healing Limits injury I have given an example of what happens after a peripheral nerve injury. Nerve injury recruits and activates immune cells at sight of lesion in DRG and in ventral and dorsal horns of spinal cord. Macrophages, T lymphocytes and mast cells invade lesion, schwann cells proliferate, an dedifferentiate and form bands to guide regenerating axons. In the DRG, macrophage and Tcells proliferate and macrophages also move within the sheath that satellite cells form around cell bodies of sensory neurons. and the satellite cells also proliferate and become active. About one week after injury, in the spinal cord, dense clusters of microglia that surround sensory and motor neurons become activated, and astrocytes are also activated which lead to release of inflammatory mediators that contribute to pain. In normal healing glia return to inactive state, however sometimes there can be long lasting changes which include structural alterations, cell proliferation, loss of neurotransmitter or ion buffering capacities, release of proinflammatory or proalgesic mediators and neurotoxicity. Pro-inflammatory events Chronic activation Neuronal death Chronic pain Scholz and Woolf (2007) Nature Neuroscience 10:11; 1361 © EJ Visser and UNDA 2018 all rights reserved

Neuroinflammation Neuroinflammation is defined as inflammation of a nerve or parts of the nervous system (CNS and PNS) Caused by activation of glia and infiltration of immune cells Can modulate excitatory and inhibitory synaptic transmission leading to enhanced chronic pain Pro-inflammatory mediators This overlaps with neuroinflammation occurs in the CNS and PNS and characterized by infiltration of leukocytes and increased production of inflammatory mediators at these sites. In particular, neuroinflammation manifests as activation of glial cells as mentioned before, activation of glial cells leads to the production pf proinflamm mediators that can powerfully modulate excitatory and inhibitory synaptic transmission, leading to central sensitization and enhanced chronic pain states. Another system that is involved in nociception and chronic pain is the adrenergic receptors Increased release of glutamate and ATP leads to disturbances in Ca2+ signalling, increased production of cytokines and free radicals, attenuation of the astrocyte glutamate transport capacity, and conformational changes in the astrocytic cytoskeleton, the actin filaments, which can lead to formation and rebuilding of new synapses. New neuronal contacts are established for maintaining and spreading pain sensation with the astrocytic networks as bridges. Thereby the glial cells can maintain the pain sensation even after the original injury has healed, and convert the pain into long-term by altering neuronal excitability. It can even be experienced from other parts of the body. Chronic pain © EJ Visser and UNDA 2018 all rights reserved

Adrenergic receptors G-protein coupled receptors Bind catecholamines- e.g. adrenaline, noradrenaline Several types- beta and alpha expressed throughout body Alpha- 1 and 2 expressed in neurons and implicated in nociception and pain Alpha-2 agonists are used to treat pain – inhibit release of noradrenaline Alpha-1 receptors expressed in keratinocytes, nerve fibres and blood vessels of skin- implicated in maintenance of chronic pain Noradrenaline Other systems that are implicated in pain are the Adrenergic receptors. Adrenergic receptors are G-protein couple receptors that bind catecholamines such as adrenaline and noradrenaline. You might be familiar with their involvement in modulating smooth muscle contraction. There are several types including beta and alpha adrenergic receptors, but alpha adrenergic receptors are expressed in neurons and implicated in nociception and pain. Alpha 2 receptors are expressed pre-synaptically and activation results in a negative feedback loop that supresses release of noradrenaline. Alpha-2 agonists such as clonidine are often used to treat pain as it binds and inhibits release of noradrenaline. Alpha-1 receptors are located on the post-synaptic neuron. © EJ Visser and UNDA 2018 all rights reserved

Alpha1-adrenergic receptors and neuropathic pain
Peripheral nerve injury Up-regulation of alpha1-adrenoceptors on nociceptive nerves and keratinocytes Activation of sympathetic nervous system Heightened nociceptor excitability and inflammation Functional changes in sympathetic activity Release of inflammatory mediators from keratinocytes Breaching of blood-nerve barrier permits alpha1- adrenoceptor activation on nociceptive afferents © EJ Visser and UNDA 2018 all rights reserved

Red heads & pain MCR 1 receptor gene (RR) (CS16)
MSH receptor polymorphism Less pricking & pressure pain More cold sensitive More sensitive to morphine Less sensitive to GA, LA

Neural mechanisms of pain

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